Current and future advances in practice: aromatase inhibitor–induced arthralgia

Abstract Aromatase inhibitors (AIs) have shown great success as adjuvant therapy for post-menopausal women with hormone receptor–positive breast cancers. AI-induced arthralgia (AIA) is a frequent AI toxicity contributing to non-adherence and discontinuation. This review aims to understand current knowledge of AIA. The mean incidence of AIA was 39.1% and the mean discontinuation of AI therapy due to AIA was 9.3%. Most of the AIAs were non-inflammatory. A shorter time since the last menstrual period and pre-existing joint pain were risk factors. Vitamin D3 supplementation may be a preventative measure and treatment with duloxetine, acupuncture and/or exercise is supported by large randomized controlled trials. There was consistent improvement in AIAs with switching to an alternate AI, and this could additionally allow continuation of cancer treatment with AI. Further research is needed to identify predictive biomarkers, better characterize AIA subcategories and study more reliable therapeutic options.


Introduction
Breast cancer is the most commonly diagnosed malignancy in women, and 70% are hormone receptor positive (HR þ ).Current treatment guidelines recommend aromatase inhibitors (Ais) as adjuvant therapy for post-menopausal women with HR þ breast cancers [1].AIs are the preferred treatment because AIs have prolonged disease-free survival compared with the selective oestrogen receptor modulator tamoxifen [2].Despite their proven efficacy, AIs have been associated with discontinuation rates as high as 32.4% [3-5], with adverse effects being the most common reason for drug discontinuation [6].With the latest guideline recommending extended AI therapy up to 10 years in high-risk disease, reducing AI toxicity and achieving the greatest drug tolerance should be a high clinical priority [1,7].Of all the AI toxicities, joint pain is noted to be the most common reason for ceasing AI therapy [6], with an estimated prevalence of 46% [8].Joint pain that develops or worsens after AI therapy initiation is grouped together under the terminology AI-induced arthralgia (AIA) [9].AIA contributes to non-adherence and premature AI discontinuation, both of which are associated with higher breast cancer recurrence rates and worsened mortality [10,11].
Given the lack of clinical guidelines on diagnosis, prevention and management of AIA symptoms, our review aims to better elucidate the current understanding of AIA and provide insights to upcoming clinical and research developments within this field.

Methods
A literature search was performed from the MEDLINE/ PubMed database and studies published up to March 2023 were included.Search terms included 'aromatase inhibitor induced arthralgia', 'arthritis', 'anastrozole', 'letrozole' and 'exemestane'.Initial screening was done based on the titles and abstracts, and any articles with a primary focus of 'joint pain', 'joint stiffness', 'AI-induced musculoskeletal symptoms', 'AI-associated arthralgia', 'arthritis' or 'AI-induced arthralgia' were included.In-depth full-text screening was performed and the types of studies included were letters to editors with original data, case reports, case series, prospective cohort studies, retrospective cohort studies and randomized controlled trials (RCTs).Any studies that did not address AI-induced arthralgia in breast cancer patients, feasibility studies, pilot studies in which a more recent version was available, reviews, correspondence articles, letters to editors without original data and duplicate studies were excluded.Screening of abstracts and titles was performed using Sciwheel (Technology from Sage, London, UK).Descriptive statistics were used for data analysis.

Results
Of the 185 publications screened, 122 were excluded according to the exclusion criteria.From the 63 publications selected for the review, 15 were prospective RCTs, 33 were prospective observational studies, 12 were retrospective observational studies and 3 were case reports (Fig. 1).

Characteristics of arthralgia
Among 23 publications that reported the incidence of AIA (Table 1), the mean incidence of AIA was 39.1%.Among studies reporting the number of joints affected, four of five studies reported the mean number of joints affected to be oligoarticular (fewer than five joints) whereas one study reported polyarticular (more than five joints).The most commonly affected joints were the hands/wrists, knees, back, hips, ankles/feet and others (shoulders, elbows, neck), in descending order.The mean time to onset of AIA was 4.5 months after AI initiation.The most frequently used methods of assessment of arthralgia were the Brief Pain Inventory (BPI), Western Ontario and McMaster Osteoarthritis Index (WOMAC), visual analogue scale (VAS), Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH) and selfadministered questionnaire (specifically designed for the study), in descending order (Table 2).

Inflammatory arthritis
According to Shanmugam et al. [20], no significant differences were seen in 28-joint DAS (DAS28) scores or inflammatory markers between those who developed AIA and controls, indicating a predominantly non-inflammatory aetiology for patient's joint pain.In the same study, two patients had a diagnosis of RA and two with Sjogren's disease prior to AI initiation; however, the same number of patients with autoimmune diseases was found in the group who developed AIA and the group who did not, indicating that pre-existing autoimmune diseases were not consistently associated with development of AIA [20].

Discontinuation due to arthralgia
The mean percentage of subjects who discontinued AI therapy due to AIA was 9.3%.One of the studies reported that 10 of 17 (58.8%)patients with AIA experienced resolution of the symptoms on average 3 months after cessation and 2 of 17 (11.8%)patients experienced a >50% reduction in pain scores [35].

Impact of menopause and menstruation
As reported in Table 3, a shorter time since the last menstrual period (<5 years) [25,32], a shorter time since menopause [33] and worse menopausal symptoms at baseline [29] were  Current and future advances in practice: AI-induced arthralgia associated with a higher incidence of AIA (all three factors had P-values <0.05).

Previous treatments
Prior opioids, NSAIDs or acetaminophen use were significant risk factors for AIA, as was prior receipt of adjuvant chemotherapy or radiation therapy [16,33].Prior tamoxifen use was specifically associated with discontinuation of AI due to AIA [15].

Type of AI
There were only two studies that reported an association between the type of AI and the incidence of AIA, and they had mixed results.One study reported a higher incidence of AIA with steroidal AIs when compared with non-steroidal AIs [36], while another study reported a higher risk of AIA with letrozole [16].

Genetic factors
One study found that single nucleotide polymorphisms were located in genes involved in the metabolism of oestrogens and vitamin D. In particular, the CYP17A1 and VDR genes were significantly associated with a higher incidence of AIA, and the CYP27B1 gene was related to AI discontinuation [31].Another study reported a greater incidence of AIA and pain severity with patients carrying the G allele of rs2073618 in the osteoprotegerin gene [37].

Protective factors against AIA
Vitamin D level There were mixed findings regarding the effect of vitamin D level on AIA (Table 4).Three studies reported that having vitamin D3 levels ≥40 ng/ml was associated with attenuated joint pain or lower risk of AIA [38,41,43], while three studies did not find any significant association of AIA with vitamin D3 levels [39,40,42].One study also reported that patients with the VDR Fok I variant genotype (vitamin D receptor polymorphism) were less likely to develop AIA than those with the wild-type VDR [42].

Previous treatments
Prior endocrine therapy (e.g.selective oestrogen receptor modulators, luteinizing hormone-releasing hormone receptor agonists or another AI), chronic diuretic therapy and concurrent treatment with calcium or bisphosphonates were associated with lower rates of arthralgia [18,36,44].

Over-the-counter medications
Table 5 reflects studies that showed no significant benefit with omega-3 supplements when considering all patients with AIA, but a possible benefit among obese patients [45,46].Vitamin B12 supplements were associated with a reduction in pain scores among patients with AIA [48].However, vitamin D3 supplements were not associated with improvement of symptoms [49].
One patient in a case report had relief of symptoms with melatonin exposure via light-emitting diodes mounted on a cap [47].

Prescribed medications
Treatment with oral prednisolone, duloxetine, glucosamine sulphate, chondroitin sulphate and thymosin were all significantly associated with improvement of AIA [44,50,51,53,54] (Table 5).The largest study assessing AIA medical treatment was a prospective randomized trial comparing the use of duloxetine 30 mg on a 13-week treatment regimen to placebo and yielded significantly lower average joint pain scores in the duloxetine cohort compared with the placebo cohort (P ¼ 0.0002) [50].The next largest study was a prospective observational study assessing the use of glucosamine sulphate (1500 mg/day) and chondroitin sulphate (1200 mg/day) for 24 weeks, resulting in significant improvement in joint pain and function at the end of the intervention (P < 0.05) [54].A randomized trial was conducted investigating the effects of testosterone use, but neither subcutaneous nor topical administration was associated with a significant change in symptoms [52].

Complementary and alternative medicine (CAM)
While many forms of alternative medicine have been investigated as treatment for AIA, the most robust data have been found for acupuncture.Four RCTs showed a significant reduction in AIA symptoms with acupuncture sessions [56][57][58][59].
One study was done on auricular point acupressure, a type of acupuncture that does not use needles, which also improved symptoms [60].Other therapies described were Kampo therapy (Japanese traditional medicine) [63], Ruta graveolens and Rhus toxicodendron (types of homeopathic medicines) [64] and tart cherry concentrate [66], which all resulted in either complete resolution or a reduction of AIA symptoms.
One study reported significant improvement in pain with massaging topical oil onto affected joints [62].However, a study that looked at the effect of all CAM treatments, not a particular treatment, did not find any difference in pain between the control and CAM groups [65].

Switching to a different AI
None of the observational studies or RCTs included in this review directly studied the effect of switching to a different AI.However, in the prospective study done by Boonstra et al. [17], two of three patients who switched to a different AI due to AIA experienced an improvement of symptoms, while in the retrospective study done by Moscetti et al. [34], all 19 patients who switched to a different AI experienced alleviation but not complete resolution of symptoms.In one case report, a patient experienced resolution of AIA symptoms after switching from anastrozole to letrozole and reported longterm adherence afterwards [74].

Relationship between AIA and cancer outcome
In a retrospective study of 1502 patients, patients who experienced AIA symptoms had significantly improved overall survival (P < 0.01) and cancer-free survival (P < 0.001) than patients who did not report AIA symptoms [22].

Discussion
AIAs are common, occurring on average in up to 40% of patients, leading to increased symptom burden, drug nonadherence and discontinuation of therapy.Although there are a limited number of studies, most cases were noninflammatory in character.A shorter time since the last menstrual period [25,32] and pre-existing joint pain [13,16,21,26] have been consistently associated with a higher risk of developing AIA.Prior exposure to certain medications or therapies, including pain medications, endocrine therapies, chemotherapy and radiation, has also been reported to be associated with AIA development [16,33].A few studies described preventative factors, including serum vitamin D3 levels, but results are inconsistent and larger studies are needed.Among treatment options, duloxetine, acupuncture and exercise have been associated with decreased arthralgia and are supported by RCTs.There is no consensus regarding the relationship between AIA development and tumour outcomes [22,76,77].
The exact mechanism of AIA remains unclear, but it is likely that more than one pathway is involved.Most mechanisms involve an oestrogen deprivation state [78].Oestrogen is known to suppress inflammatory cytokine production.Similar to arthralgia that manifests in perimenopausal women, AIA may be caused by oestrogen deprivation, leading to the production of inflammatory cytokines in joint chondrocytes [79].Moreover, a reduction of antinociceptive effects of oestrogen in a low-oestrogen state may lower the pain threshold in patients, making them more susceptible to developing arthralgia [80].Accelerated bone loss from oestrogen deprivation likely also contributes to AIA and explains the higher incidences of osteopenia and osteoporosis found in AIA [81].Lastly, given the higher incidences of AIA in those with a shorter time since the last menstrual period [25,32], rapid fluctuation in the oestrogen level rather than the absolute oestrogen level may contribute to AIA.Based on the review and potential mechanisms, below are our proposed recommendations.Educating patients prior to the start of AIs can encourage greater adherence and empower patients to be more vigilant about their potential toxicity.Although high-powered prospective studies are still lacking, there are data that identify some modifiable risk factors (high BMI, pre-existing joint pain) that may be addressable prior to the start of AI treatment to reduce the chances of AIA [17,29].Patients may be additionally motivated to seek out healthier eating and/or exercise if they know that a higher BMI may contribute to AIA development.
The chances of inflammatory arthropathy with AI treatment are very low; physical exam findings and laboratory or imaging results should be carefully assessed for the presence of inflammation, as a lack of inflammation may help avoid deleterious side effects of inappropriately prescribed modalities such as systemic steroids.In those with AIA, exercise or physical therapy should be offered as the first line of therapy.Various over-the-counter agents such as acetaminophen and NSAIDs can be used as adjuncts for pain management.If pain is still poorly controlled, we recommend trialling duloxetine as long as there are no contraindications.Vitamin D supplements should be recommended (being low risk when taken in recommended doses).A DXA scan should be done, if not done already, and bisphosphonates for patients with osteopenia or osteoporosis should be offered if appropriate [38,41,43].Switching to an alternate AI is a good therapeutic strategy, as numerous studies have reported on the resolution or attenuation of AIA symptoms after switching to a different AI [82].Additionally, research has shown better cancer outcomes with AIs vs tamoxifen, so we recommend alternate AIs before switching to tamoxifen [2, 7].Lastly, regular follow-ups are crucial for monitoring pain control and ensuring compliance to AI treatment.

Future directions
Further study is needed for both assessment and management of AIAs.Translational studies to elucidate serologic markers as well as synovial tissue analysis of the affected joint(s) can yield a better understanding of AIA pathophysiology and further assist in identifying potential subcategories of AIA.Additionally, identifying validated tools to properly characterize AIAs and creating a unified terminology with consistent methods of assessment will facilitate future clinical trials.There is a paucity of reliable AIA management options and preventative therapies.Various supplements and prescribed medications have been suggested, but RCTs should be performed to validate their efficacy.All in all, AIA affects a significant portion of patients on AI therapy, with the severity limiting treatment adherence in some patients.An improved understanding of the diagnosis and management of this disorder is necessary to improve patient tolerance and quality of life.

Figure 1 .
Figure 1.Of the 185 publications screened, 122 were excluded according to the exclusion criteria and ultimately 63 publications were selected for the review

Table 2 .
Methods of assessment

Table 4 .
Protective factors for AIA CR: case report; OTC: over the counter; BPI-SF: Brief Pain Inventory-Short Form; O3-FA: Omega-3 fatty acid; BCPT-MS: Breast Cancer Prevention Trial-Musculoskeletal Symptom Scale; M-SACRAH: Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands; EA: electroacupuncture.Current and future advances in practice: AI-induced arthralgia